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Granulomatosis With Polyangiitis

Granulomatosis with polyangiitis (GPA), previously called Wegener's granulomatosis, is a rare disease in which blood vessels and other tissues become inflamed. This inflammation limits blood flow to important organs in the body, potentially leading to long-term damage. Disease onset and severity varies between patients, and earlier diagnosis and treatment can prevent life-threatening organ failure.

Although the disease can involve any organ system, GPA mainly affects the respiratory tract (sinuses, nose, trachea [windpipe], and lungs) and kidneys. This disorder can affect people at any age and strikes men and women equally. Compared to other racial groups, Caucasians are more commonly affected.

Cause

Health experts do not know what causes GPA.

Symptoms

Upper respiratory tract

The most common sign of GPA is upper respiratory tract distress such as sinus pain, discolored or bloody fluid from the nose, and nasal ulcers. A common sign of the disease is almost constant rhinorrhea (“runny nose”) or other cold symptoms that do not respond to usual treatment or become increasingly worse. It is important to note that other more common diseases (such as allergies) can produce constant rhinorrhea, and GPA is a rare cause of this symptom.

Rhinorrhea in GPA results from nasal inflammation or sinus drainage and can cause pain. A hole may develop in the cartilage of the nose, which may lead to collapse (called saddle-nose deformity). The eustachian tubes, which are important for normal ear function, may become blocked, causing chronic ear problems and hearing loss. Bacterial infection can complicate GPA-related sinusitis (inflammation of the sinuses) with congestion and chronic sinus pain.

Lungs

The lungs are affected in most people with GPA, although no symptoms may be present. If symptoms are present, they include cough, hemoptysis (coughing up blood), shortness of breath, and chest discomfort.

Kidneys

Kidney involvement, which occurs in more than three-fourths of people with this disorder, usually does not cause symptoms. If detected by blood and urine tests, a healthcare professional can start proper treatment, preventing long-term damage to the kidneys.

Musculoskeletal system

Pain in the muscles and joints and occasional joint swelling affects two-thirds of people with GPA. Although joint pain can be very uncomfortable, it does not lead to permanent joint damage or deformities.

Eyes

GPA can affect the eyes in the following ways:

Conjunctivitis (inflammation of the inner lining of the eyelid)

Scleritis (inflammation of the sclera, or the white part of the eyeball)

Episcleritis (inflammation of the outer surface of the sclera)

Lesions behind the eyeball

Eye symptoms also include redness, burning, or pain. Double or reduced vision is a serious symptom requiring immediate medical attention.

Skin lesions

Nearly half of people with GPA develop skin lesions. These often have the appearance of small red or purple raised areas or blister-like lesions, ulcers, or nodules that may or may not be painful.

Other symptoms

Some people with GPA experience narrowing of the trachea. The symptoms can include voice change, hoarseness, shortness of breath, or cough.

The nervous system and heart occasionally may be affected. Fever and night sweats may occur. Fever also may signal an infection, often of the upper respiratory tract.

Diagnosis

To treat people with GPA most effectively, healthcare professionals must diagnose the disease early. There are no blood tests to diagnose GPA, but blood tests are important to rule out other causes of illness and to determine which organ may be affected.

Most blood tests can only suggest that a person has inflammation somewhere in the body. Anemia (low red blood cell count), elevated platelet and white blood cell counts, and a higher red blood cell sedimentation rate - all indicators of inflammation - are commonly found in people with GPA. If the kidneys are involved, a healthcare professional can see red blood cells and structures called red blood cell casts in the urine when viewed under a microscope, and blood tests measuring kidney function may show abnormalities.

X-ray results can be very helpful in diagnosing GPA. People with lung problems will have abnormal chest X-rays. CT (computed tomography) scans in people with sinus problems may show thickening of the sinus lining.

Many people with active GPA have a blood test that shows the presence of proteins called antineutrophil cytoplasmic antibodies (ANCA). Although a positive ANCA test is useful to support a suspected GPA diagnosis, healthcare professionals typically do not use it alone to diagnose this disorder. The ANCA test may be negative in some people with active GPA.

Currently, the only clear-cut way to diagnose GPA is by performing a biopsy (removing a tiny piece of tissue) of an involved organ. A healthcare professional will examine tissue from the organ under the microscope to confirm the presence of vasculitis and granulomas (a specific type of inflammation), which together are features of GPA. A biopsy is very important both to confirm the presence of the disorder and to rule out other disorders that may have similar signs and symptoms.

Treatment

With the appropriate treatment, the outlook is good for people with GPA. In a study of 158 patients who were treated with prednisone and cyclophosphamide at the National Institutes of Health (NIH), 91 percent markedly improved. After 6 months to 24 years of follow-up, 80 percent survived.

In most cases, treatment consists of a combination of a glucocorticoid (a steroid) and a cytotoxic (cell-damaging) medicine. Although these medicines are helpful in treating GPA, they have potentially serious side effects. In many instances, healthcare professionals can minimize or prevent side effects through careful monitoring using laboratory tests and imaging tools.

Approximately half of people with GPA may experience a return of their disease, commonly referred to as a relapse. This occurs most frequently within 2 years of stopping treatment, but can occur at any time. Thus, it is extremely important that people continue to see their healthcare professionals regularly, both during treatment as well as after they have stopped taking medication.

Prednisone

Prednisone is a glucocorticoid that healthcare professionals commonly prescribe for GPA. Prednisone is similar to cortisol, the natural glucocorticoid hormone produced by the body. However, it is chemically different from the anabolic steroids that have been used by athletes. It also is administered in doses much higher than the body normally produces.

Healthcare professionals usually give prednisone as a single morning dose to try to imitate how the body normally secretes cortisol. When a person's illness improves, the prednisone dose is gradually decreased and converted to an every-other-day dosing schedule, usually over a period of 3 to 4 months. With further improvement, prednisone is gradually decreased and discontinued completely after approximately 6 to 12 months.

When a person takes prednisone by mouth, the body stops making cortisol. As the prednisone dose is gradually reduced, the body will resume making cortisol. It is extremely important that prednisone never be stopped suddenly because the body needs prednisone (or cortisol) to function.

Prednisone can affect the body's ability to fight off infection. People taking this medicine should immediately report any symptoms of infection and fever to their doctors. Prednisone also can cause weight gain, cataracts, brittle bones, diabetes, and changes in mood and personality.

Cyclophosphamide

Cyclophosphamide (Cytoxan) is the cytotoxic medicine most commonly used to treat GPA. People take cyclophosphamide once a day by mouth. They must take the medicine all at once in the morning, and then drink a large amount of liquid. Although the first dose of cyclophosphamide is based on the person's weight and kidney function, a healthcare professional may adjust the dosage based on blood counts, which are monitored closely to ensure the white blood cell count remains at a safe level.

In the original standard of care, cyclophosphamide was continued for a full year beyond disease remission. The dose of cyclophosphamide was then decreased gradually and eventually stopped. In more recent treatment approaches, however, cyclophosphamide is either not used at all or given only to patients with severe disease. When cyclophosphamide is used, it is only administered until remission is achieved and then substituted by another, less-toxic medication such as methotrexate or azathioprine (see below).

Cyclophosphamide is a powerful medicine that keeps the immune system from working normally. Healthcare professionals must monitor their patients carefully and frequently check blood cell counts. Cyclophosphamide can cause an increased risk of infection, bone marrow suppression (lowering of blood counts), sterility, hemorrhagic cystitis (bleeding from the bladder), and bladder cancer, as well as other serious side effects.

Methotrexate

Researchers at NIH have been studying the use of methotrexate to treat GPA since 1990. In people with active, but not immediately life-threatening, GPA, methotrexate has been used in combination with prednisone to induce remission. It also is used to maintain remission after a person has initially received cyclophosphamide. Methotrexate is usually given for 1 to 2 years. If remission holds, the dosage is lowered and eventually stopped.

Methotrexate is given once a week usually by mouth, but occasionally as an injection under the skin or in the muscle. People taking methotrexate need to have regular blood work to monitor their response and to watch for side effects.

The side effects of methotrexate include infection, lowering of blood cell counts, nausea, soreness and ulceration of the mouth lining, irritation of the lungs (pneumonitis), and inflammation and scarring of the liver. People taking methotrexate cannot drink alcoholic beverages. Methotrexate cannot be given to people who have poor kidney function or who have underlying liver disease such as hepatitis.

Azathioprine

Healthcare professionals use azathioprine (also called Imuran) primarily to maintain remission in people who have initially been treated and gone into remission with cyclophosphamide. Azathioprine is taken once a day by mouth. Similar to methotrexate, it is usually given for 1 to 2 years. If remission holds, the dosage is lowered until it is stopped.

The side effects of azathioprine include infection, decreased blood cell counts, and rarely an allergic-type reaction. In transplant recipients, the drug has been associated with an increased risk of blood cancers (leukemia and lymphoma). Whether this risk exists in other situations is unclear. People with poor kidney function or liver disease can take azathioprine.

Rituximab

Rituximab is an antibody that selectively reduces specific types of immune cells (B cells) circulating in the blood. It currently is used to treat certain types of lymphoma and rheumatoid arthritis. Recent studies suggest that rituximab, when given along with prednisone, effectively induces remission in select GPA patients. In April 2011, the FDA approved rituximab, in combination with glucocorticoids, for treating GPA. Researchers are currently studying the long-term effects of rituximab on maintaining remission. Thus far, participants of the study have been monitored for 18 months, and rituximab continues to be as effective as the standard regimen (cyclophosphamide with azathioprine) in maintaining remission.

Research

Research physicians at NIAID have studied GPA since the 1970s. NIAID scientists first introduced the combination of glucocorticoids and cyclophosphamide for treating people with the disease. While this was a dramatic breakthrough for the treatment of GPA, researchers realize that these medicines have serious side effects and cannot be tolerated by all people. Therefore, NIAID has sponsored clinical trials examining the effectiveness of new therapies, such as rituximab.

NIAID and other parts of the National Institutes of Health support research on GPA and related forms of vasculitis at medical centers throughout the United States through the extramural grants program. NIH supports the Vasculitis Clinical Research Consortium (VCRC), for example. The multicenter VCRC fosters and facilitates clinical investigation in the inflammatory vasculitides, including GPA.

NIAID and other components of the National Institutes of Health support research on GPA and related forms of vasculitis at medical centers throughout the United States. For example, NIH supports the Vasculitis Clinical Research Consortium (VCRC), which facilitates clinical investigation in the inflammatory vasculitides, a group of disorders characterized by inflammation of blood vessels, including GPA.

The VCRC includes the following clinical centers:

Boston University School of Medicine, Massachusetts

Ceders-Sinai Medical Center, Los Angeles, California

Cleveland Clinic, Ohio

Hospital for Special Surgery, New York, New York

Mayo Clinic College of Medicine, Rochester, Minnesota

Mt. Sinai Hospital, Toronto, Ontario

St. Joseph’s Hospital, Hamilton, Ontario

The University of Pennsylvania, Philadelphia

The University of Pittsburgh, Pennsylvania

The University of Utah, Salt Lake City

The University of California, San Francisco

See more information about the VCRC. Much of the information available at this site is designed to help people manage their disease.